2,2-Dialkyltetrahydropyrans

ABSTRACT

By treating a primary or secondary alkenol having an olefinic bond in the sixth position relative to the carbon atom carrying the hydroxyl group and at least one methyl group in the fifth position relative to said carbon atom with a strong acid (e.g., 85 percent phosphoric acid), 2,2-dialkyltetrahydropyrans are produced via a cyclization reaction. The products have desirable fragrance characteristics.

Methods for the synthesis of 2,2-dialkyltetrahydropyrans have beenreported in the literature. In Bull. Soc. Chim. France 1971, No. 10 atpages 3501-8, Combret et al. describe a Grignard synthesis in which2,2-dialkyltetrahydropyrans may be produced in systems in whichhexamethylphosphoramide is used as the solvent. In Ann. Chim. (Pairs) 131, 436-474 (1956), Crisan shows that 2,2-dialkyltetrahydropyrans areobtained by slowly distilling primary alkenols having an olefinic bondin the fourth or fifth position relative to the carbon atom carrying thehydroxyl group with phosphoric acid. See also Chemical Abstracts 51,5059-5061 (1957).

In accordance with this invention, it has been found that2,2-dialkyltetrahydropyrans can be readily produced by contactingcertain methyl substituted primary or secondary alkenols with a strongacid so that cyclization occurs, the alkenols being characterized byhaving an olefinic bond in the sixth position relative to the carbonatom carrying the hydroxyl group and at least one methyl group in thefifth position relative to said carbon atom.

Exemplary alkenols include 5-methyl-6-hepten-1-ol,5,6-dimethyl-6-hepten-1-ol, 2,5-dimethyl-6-hepten-1-ol,6-ethyl-5-methyl-6-hepten-1-ol, 6-methyl-7-octen-2-ol,6,7-dimethyl-7-octen-2-ol, 7-ethyl-6-methyl-7-octen-2-ol,7-methyl-8-nonen-3-ol, 5-methyl-6-(4-methyl-3-pentenyl)-6-hepten-1-ol,5,5,6-trimethyl-6-hepten-1-ol and the like. Suitable procedures for thesynthesis of such alkenols are described for example in U.S. Pat. Nos.3,493,623 and 3,631,065.

Phosphoric acid is the preferred strong acid for use in the process.However, if desired, use may be made of such other acids aspolyphosphoric acid, benzene sulfonic acid, toluene sulfonic acid, HCl,H₂ SO₄, and the like.

The process is normally conducted at room temperature since thecyclization reaction is relatively facile at such temperatures. In manycases the reaction proceeds cleanly and in high yield by treating thealkenol with the acid for as little as an hour or less at roomtemperature. For best results the acid and the alkenol should beconstantly mixed or agitated such as by stirring or shaking. If desired,mildly elevated temperatures (e.g., up to about 100° C.) may be used inorder to enhance reaction rate. Care should be taken however not to heatthe reaction mixture to a temperature at which undesired side reactionssuch as oxidation take place. Conversely, it is possible to perform thecyclization reaction at temperatures below room temperature, and in somecases this may be found desirable in suppressing undesired sidereactions. Thus temperatures as low as 0° C. or below may be used inappropriate circumstances. Naturally the system should be allowed tointeract for a sufficient period for the cyclization to occur.

The 2,2-dialkyltetrahydropyrans produced by the process of thisinvention have desirable fragrance characteristics and thus may be usedas perfumes or odorants in a variety of products, such as sanitizingsolutions, kitchen and bathroom cleansers, furniture polishes, laundrydetergents, wax candles and like scented products. They are also usefulas complexing solvents.

The practice of this invention will become still further apparent from aconsideration of the ensuing illustrative examples.

EXAMPLE I 2-isopropyl-2-methyltetrahydropyran

A 2.0 gram sample of 80 to 20 weight percent mixture of5,6-dimethyl-6-hepten-1-ol and 5,5-dimethyl-6-hepten-1-ol was stirredwith 85 percent phosphoric acid at room temperature for one hour. Duringthis time all of the 5,6-dimethyl-6-hepten-1-ol was converted to2-isopropyl-2-methyltetrahydropyran, 1.0 gram of which was isolated andanalyzed. Its structure was verified by NMR, IR and mass spectrographicanalyses. The NMR spectrum showed that the product contains an isopropylgroup, an unsplit methyl group, a methylene group (triplet) adjacent toan oxygen atom and six other methylene protons. The IR spectrum showedan absence of hydroxyl and olefinic groups. The mass spec crackingpattern gave a small parent peak at mass 142, a 100 percent peak at 99,and principal peaks at 127 (10 percent), 87 (11 percent), 71 (18percent), 55 (16 percent), and 43 (˜100 percent).2-Isopropyl-2-methyltetrahydropyran has a boiling point of 85° C. at 45millimeters mercury pressure. It has a characteristic minty fragrance.

The conversion of the alkenol to the cyclic ether is best explained by aprotonation step followed by a 1,2-hydride shift (protonelimination-addition) to produce a new tertiary carbonium ion whichundergoes ring closure with proton elimination: ##STR1##

Under the conditions used the 5,5-dimethyl-6-hepten-1-ol was notparticularly reactive and thus for the most part remained unchanged.More rigorous conditions should convert this less reactive alkenol tothe same cyclic ether product, viz.,2-isopropyl-2-methyltetrahydropyran. This transformation would occurthrough conversion of the alkenol to a secondary carbonium ion followedby a 1,2-methyl migration (Nametkin rearrangement--see J. H. Berson,"Molecular Rearrangements", Vol. I, edited by Paul de Mayo, 1963,Interscience Publishers, New York, p. 155) to produce the tertiarycarbonium ion which then undergoes the observed ring closure to thedesired product: ##STR2##

EXAMPLE II 2-ethyl-2-methyltetrahydropyran

A series of experiments was conducted in which 5-methyl-6-hepten-1-olwas treated with 85 percent phosphoric acid under various conditions.Each reaction was followed by vapor phase chromatography (v.p.c.). Ineach case, after the specified reaction time the mixtures were dissolvedin cold diethyl ether, washed with water, aqueous sodium bicarbonate andwater again, dried over anhydrous magnesium sulfate and then injectedinto a v.p.c. Reaction conditions and results of the experiments are setforth in the ensuing table. The unchanged alkenol peak occurred at 225°C. and the peak at 155° C. represented the desired product,2-ethyl-2-methyltetrahydropyran. In some of the experiments a peak at180° C. was observed and this was found to represent 5-methylheptanalformed by means of an intramolecular 1,5-hydride shift. The productionof aldehydes from an olefinic alcohol or a tetrahydropyran by means ofan intramolecular 1,5-hydride shift has apparently not been reported inthe literature heretofore. Other peaks were noted at 115° C., 165° C.,and 230° C. These represented unknown products and impurities.

                  TABLE                                                           ______________________________________                                        Cyclization of 5-methyl-6-hepten-1-ol                                                       Percentages of                                                                Components as Determined                                        Reaction Conditions                                                                         by Temperature Programmed V.P.C.                                Reaction Time,                                                                Temperature                                                                            Minutes  155° C.**                                                                         180° C.**                                                                      225° C.**                         ______________________________________                                        RT*       5        5%        --      88.5%                                    RT*      20       13%        --      83%                                      RT*      45       92%        --      --                                       75       10       91%        6.5%    --                                       75       20       77%        20%     --                                       90       45       24%        22%     --                                       ______________________________________                                         *Room Temperature                                                             **Elution temperature for 1/4" × 15' Carbowax 20M column programmed     from 80° - 237° C. at 10°/min.                      

It can be seen from the above table that when using phosphoric acid thecyclization reaction should be performed at a temperature in the rangeof from about 20° C. to about 75° C. with the reaction time adjustedaccordingly.

The following example illustrates an embodiment of this inventionwherein 2 ring closures occur by effecting contact between a strong acidand a 5-methyl-6-hepten-1-ol in which the sixth position carries analkenyl group having a double bond in its third position. In thisinstance, the reaction does not proceed as cleanly nor in as high ayield as when using the simple alkenols having only one double bond inthe molecule. Nevertheless, the product in the following examplerepresents a unique compound having useful fragrance characteristics.

EXAMPLE III 2-methyl-2-(3', 3'-dimethylcyclohexyl)-tetrahydropyran

The procedure of Example I was applied to a sample of5-methyl-6-(4-methyl-3-pentenyl)-6-hepten-1-ol. This was stirred with 85percent phosphoric acid for one hour at room temperature, and theether-soluble, water-insoluble reaction product was chromatographed onalumina. A relatively non-polar material was eluted from the columnimmediately (polar materials such as alcohols remained on the column).The eluted product was identified by means of NMR and IR as2-methyl-2-(3', 3'-dimethylcyclohexyl)-tetrahydropyran.

In the process the cyclohexyl ring is produced first, followed by a1,2-hydrogen shift and finally closure of the alcohol to form the cyclic6-membered ether: ##STR3## The temperature-programmed v.p.c.chromatogram showed a single peak (Carbowax 20M, Chromosorb P, Max. T237° C., 1/4"×15'); however, on isothermal operation, 237° C., the peakappeared as a poorly resolved doublet with the components present inabout equal amounts. It is highly likely that this doublet representsthe resolution of the compound into its two stereochemical (geometrical)isomers: ##STR4## These compounds represent about 50 percent of theproduct, the remainder was alcohols retained on the alumina column. Thev.p.c. analysis of the alcohols indicated a complex mixture and noattempt was made at further separation or identification.

EXAMPLE IV 2,6-dimethyl-2-isopropyltetrahydropyran

A 2.0 gram sample of a mixture of isomeric C₁₀ -olefinic alcohols wasstirred for 25 minutes at room temperature with 85 percent phosphoricacid. This alcohol mixture (produced by hydrolysis of thecleavage/condensation product from reaction of1-isobutyl-3-methyl-aluminacyclopent-3-ene with2-methyltetrahydrofuran--note U.S. Pat. No. 3,631,065) was composed of:

    ______________________________________                                        6,6-dimethyl-7-octen-2-ol                                                                             (30%)                                                 6,7-dimethyl-7-octen-2-ol                                                                             (57%)                                                 6,7-dimethyl-6-octen-2-ol                                                                              (6%)                                                 4,5,6-trimethyl-6-hepten-1-ol                                                                          (7%)                                                 ______________________________________                                    

This acid-catalyzed cyclization produced two new compounds. These newcompounds which were poorly resolved on a Carbowax 20M column, had aretention temperature of 150° C. compared with about 220° C. for thestarting material. Unreacted alcohol comprised 28 percent of the productmixture. The alcohol was removed on an Al₂ O₃ /Et₂ O column and waslater identified as 6,6-dimethyl-7-octen-2-ol (0.4 gram, 20 percent ofstarting material) by NMR and v.p.c. The materials which were elutedfrom the Al₂ O₃ /Et₂ O chromotography column were identified by NMR astwo stereochemical isomers of 2,6-dimethyl-2-isopropyltetrahydropyran(1.28 grams, 54 percent yield): ##STR5## Two small peaks (8 percent)having a retention of 170° C. were also observed and probablycorresponded to cyclic products from closure of the primary alcohol,4,5,6-trimethyl-6-hepten-1-ol.

More strenuous treatment of the mixture (1.60 grams) of the C₁₀-olefinic alcohols with 85 percent H₃ PO₄ at 110° C. for 50 minutesresulted in the isolation of 1.48 grams (yield of 83 percent) of aproduct which has a retention temperature of 205° C. on a Carbowax 20Mcolumn and was 90 percent pure by v.p.c. analyses. The material wasdistilled, b_(23mm) 96° C., and 0.95 gram of 95 percent pure materialobtained. The NMR spectrum contained a methyl-ketone resonance signaland was consistent with the structure 6,7-dimethyloctan-2-one whichprobably arises via a 1,5-hydride ion transfer which is conventional asapplied to the synthesis of ketones--see Hill and Carlson, J. Am. Chem.Soc. 87, 2772-3 (1965).

EXAMPLE V 2-methyl-2-tert-butyltetrahydropyran

1.76 grams of 5,5,6-trimethyl-6-hepten-1-ol was treated with 20milliliters of 85 percent phosphoric acid for 15 minutes at roomtemperature with stirring. All but 3 percent of the primary alkenol wasconverted to a compound having a v.p.c. retention temperature of 175° C.on a 1/4"×15' Carbowax 20M column. The primary alkenol itself had aretention temperature of 237° C. The residual primary alkenol wasremoved from the new compound formed in the reaction by chromatographingon Al₂ O₃ /Et₂ O. The ether was removed from the new compound at reducedpressure, 45 mm Hg at 27° C. The recovered material was at least 93percent pure and the NMR spectrum was consistent with the structure2-methyl-2-tert-butyl-tetrahydropyran.

The ease by which 2-methyl-2-tert-butyl-tetrahydropyran was produced(R.T., 15 minutes) is worthy of note, especially since a 1,2-methylshift is involved. As pointed out in Example I, cyclization of5,5-dimethyl-6-hepten-1-ol in which a 1,2-methyl shift would be involveddid not occur extensively at room temperature.

EXAMPLE VI 2-ethyl-2-methyltetrahydropyran

1.8 grams of 5-methyl-6-hepten-1-ol (containing 5.4 percent5-methyl-5-hepten-1-ol and 2.4 percent impurities) was reacted with 18cc of 85 percent phosphoric acid at room temperature for 3.5 hours. Thenthe solution was worked up using the procedure of Example II. The v.p.c.showed the following to be present:

84% 2-ethyl-2-methyltetrahydropyran

11% 5-methyl-6-hepten-1-ol

1% 5-methyl-5-hepten-1-ol

4% impurities

The mixture was distilled and the fraction boiling at 67° C. at 46 mm Hgwas collected. This gave 0.37 gram of 99 percent pure2-ethyl-2-methyltetrahydropyran. Its structure was confirmed by NMR andmass spectral data. The compound had an odor similar to a well knownmentholated chest rub.

From the results set forth in the above examples it can be seen that inthe process of this invention reaction proceeds via (i) protonation atthe seventh position; (ii) formation of a tertiary carbonium ion in thefifth position either via a 1,2-hydride shift (if the initial alkenolcontains only one methyl group in the fifth position) or a 1,2-methylshift (if the initial alkenol contains two methyl groups in the fifthposition); and (iii) intramolecular ring closure and proton eliminationinvolving the oxygen atom and the tertiary carbonium ion so formed, theforegoing positions being relative to the carbon atom carrying thehydroxyl group.

We claim:
 1. A process of producing 2,2-dialkyltetrahydropyrans whichcomprises contacting a methyl substituted primary or secondary alkenolwith a strong acid so that cyclization occurs, said alkenol beingcharacterized by having an olefinic bond in the sixth position relativeto the carbon atom carrying the hydroxyl group and at least one methylgroup in the fifth position relative to said carbon atom.
 2. The processof claim 1 wherein said strong acid is phosphoric acid.
 3. The processof claim 1 wherein the contacting is effected at about room temperature.4. The process of claim 1 wherein said strong acid is phosphoric acidand the contacting is effected at a temperature in the range of fromabout 20° C. to about 75° C.
 5. The process of claim 1 wherein thealkenol is 5,6-dimethyl-6-hepten-1-ol.
 6. The process of claim 1 whereinthe alkenol is 5-methyl-6-hepten-1-ol.
 7. The process of claim 1 whereinthe alkenol is 5-methyl-6-(4-methyl-3-pentenyl)-6-hepten-1-ol.
 8. Theprocess of claim 1 wherein the alkenol is one or a mixture of6,6-dimethyl-7-octen-2-ol and 6,7-dimethyl-7-octen-2-ol.
 9. The processof claim 1 wherein the alkenol is 5,5,6-trimethyl-6-hepten-1-ol.